Discovery and SAR study of hydroxyacetophenone derivatives as potent, non-steroidal farnesoid X receptor (FXR) antagonists
Discovery and SAR study of hydroxyacetophenone derivatives as potent, non-steroidal farnesoid X receptor (FXR) antagonists
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作为有效的非类固醇法尼醇 X 受体 (FXR) 拮抗剂的羟基苯乙酮衍生物的发现和 SAR 研究
DOI：
10.1016/j.bmc.2014.01.032
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发表时间：
2014-03-01
影响因子：
3.5
通讯作者：
Hu, Lihong
中科院分区：
文献类型：
--
作者：
Liu, Peng;Xu, Xing;Hu, Lihong
通过高通量筛选发现化合物1（IC 50 = 35.2 +/-7.2 μ M），一种中度FXR拮抗剂。构效关系研究表明芳香环取代基的形状和亲脂性显著影响FXR拮抗剂的活性，增加芳香环取代基的形状和亲脂性可增强FXR拮抗剂的效力。特别是，当芳环C2位的OH被OBn取代基（类似物2b）取代时，其活性可提高至IC 50 = 1.1 +/-0.1 μ M。此外，接头的长度和四唑结构对于保持活性是必不可少的。(C)2014爱思唯尔有限公司版权所有。
Compound 1 (IC50 = 35.2 +/- 7.2 mu M), a moderate FXR antagonist was discovered via high-throughput screening. Structure-activity relationship studies indicated that the shape and the lipophilicity of the substituents of the aromatic ring affect the activity dramatically, increasing the shape and the lipophilicity of the substituents of the aromatic ring enhances the potency of FXR antagonists. Especially, when the OH at C2 position of the aromatic ring was replaced by the OBn substituent (analog 2b), its activity could be improved to IC50 = 1.1 +/- 0.1 mu M. Besides, the length of the linker and the tetrazole structure are essential for retaining the activity. (C) 2014 Elsevier Ltd. All rights reserved.